COORDINATED EXPRESSION AND FUNCTION OF NEUROTROPHINS AND THEIR RECEPTORS IN THE RAT INNER-EAR DURING TARGET INNERVATION

We show that trkB and trkC mRNAS, encoding the high-affinity receptor tyrosine kinases for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), respectively, as well as low-affinity nerve growth factor receptor (p75(LNGFR)) mRNA are expressed in the cochleovestibular ganglion (CVG) before and during innervation of the target fields. Correspondingly, from preinnervation stages onward, BDNF and NT-3, but neither nerve growth factor (NGF)nor neurotrophin-4(NT-4) mRNAs are expressed in the sensory epithelium of the otic vesicle, the peripheral target field of CVG neurons. No neurotrophin transcripts were detected by in situ hybridization in the medullary central targets. In explant cultures, neuritogenesis from both the cochlear and vestibular part of the CVG was promoted by BDNF, while NT-3 evoked neurites mainly from the cochlear neurons. Also NT-4 stimulated neurite outgrowth from the CVG in vitro. In dissociated neuron-enriched cultures, NT-3 and BDNF promoted survival of overlapping subsets of CVG neurons and, correspondingly, results from in situ hybridization showed that both trkC and trkB mrnas were expressed in most neurons of this ganglion. The negligible effect of NGF seen in the bioassays agrees well with the expression of only a few trkA transcripts, encoding the high-affinity receptor for NGF, in the CVG. Based on the spatiotemporal expression patterns and biological effects in vitro, peripherally-synthesized BDNF and NT-3 regulate the survival of CVG neurons as well as the establishment of neuron-target cell contacts in the early-developing inner ear. In addition, the expression of trkB mRNA, more specifically its truncated form, and trkC as well as p75(LNGFR) mRNAS in distinct, non-neuronal structures indicates novel roles for these molecules during development.